Long-term potentiation (LTP) and its dependence upon NMDA receptor-mediated Ca[2+] entry has been widely studied as the presumptive mechanism underlying learning and memory. Numerous proteins have been implicated in the induction, maintenance, and modulation of LTP expression. This proposal adds a novel contributor, the Ca[2+]/calmodulin kinase II (CaMKII) gated Cl[-] channel ClC-3, to the regulation of LTP that is unique in its ability to modulate synaptic responses and LTP in an activity- and developmentally-dependent manner. Although ClC-3 is broadly expressed throughout the brain, the ClC-3 knockout mouse shows complete, selective postnatal neurodegeneration of the hippocampus. In fact, multiple lines of ClC-3 knockout mice exhibit similar hippocampal degeneration, suggesting a novel role of this channel in maintaining normal brain function. In support, recent preliminary studies show seizure-like activity in ClC-3 knockout mice; a role for Cl[-] channels, specifically ClC-3, in regulating excitability in the adult brain has not been studied. Prior work has demonstrated that ClC-3 is spatially and functionally linked to the NMDA receptor: NMDA receptordependent Ca[2+] entry, activation of CaMKII, and subsequent phosphorylation/gating of ClC-3 by CaMKII links the two channels via a Ca[2+]-mediated feedback loop. As a result of the shift in the Cl[-] gradient during development, we hypothesize that ClC-3 facilitates excitation and Ca[2+] influx early in development when the equilibrium potential for Cl[-] is depolarizing; conversely, ClC-3 gating suppresses excitation and Ca[2+] influx, thereby restraining the expression of LTP in adulthood when Cl[-] flux is hyperpolarizing. Thus ClC-3 is ideally suited to differentially influence synaptic plasticity as a function of Ca[2+] influx and internal [Cl[-]]. The goal of this application is to characterize the impact of ClC-3 gating on NMDA receptor currents and expression of LTP as a function of the developmentally-regulated Cl[-] gradient. The ClC-3 knockout model allows us to explore the delicate interaction between neuronal development, plasticity, excitation-inhibition balance, and long-term survival a unifying mechanism likely to be applicable in multiple contexts beyond chloride channels.